TWI436789B - Method for lyophilising particles having a pharmaceutical compound contained therein and a pharmaceutical pack containing such particles - Google Patents
Method for lyophilising particles having a pharmaceutical compound contained therein and a pharmaceutical pack containing such particles Download PDFInfo
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- TWI436789B TWI436789B TW098101784A TW98101784A TWI436789B TW I436789 B TWI436789 B TW I436789B TW 098101784 A TW098101784 A TW 098101784A TW 98101784 A TW98101784 A TW 98101784A TW I436789 B TWI436789 B TW I436789B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
本發明係關於一種包含冷凍液體之顆粒的冷凍乾燥方法，該冷凍液體具有藥學化合物於其中。本發明也關於一種藥學包，其包含容器，且該容器中具有至少一種藉由此方法所得之顆粒。The present invention relates to a freeze-drying method comprising particles of a frozen liquid having a pharmaceutical compound therein. The invention also relates to a pharmaceutical pack comprising a container having at least one granule obtained by such a method.
由EP 799613得知此種方法及藥學包。特別地，描述一種獲得具有約0.2毫米至約10毫米典型尺寸之冷凍顆粒的方法，該顆粒含有一或多種源自微生物的抗原(特別是活的或已殺死的微生物整體者，或衍生自這些微生物的亞單元者)以作為藥學化合物。這些顆粒可以被冷凍乾燥，以獲得可長時間在高於0℃下儲存而無任何明顯之效力損失的顆粒。然而此已知方法之缺點是：一批顆粒之冷凍乾燥常導致顆粒的有效含量相當大的分佈，即使正要在乾燥步驟前，冷凍顆粒在有效含量方面是極均勻的。其次，顆粒之群集可能在乾燥步驟期間發生。Such a method and pharmaceutical package are known from EP 799613. In particular, a method is described for obtaining frozen particles having a typical size of from about 0.2 mm to about 10 mm, the particles containing one or more antigens derived from microorganisms (especially living or killed microorganisms as a whole, or derived from The subunits of these microorganisms are used as pharmaceutical compounds. These granules can be lyophilized to obtain granules which can be stored at temperatures above 0 ° C for a prolonged period without any significant loss of potency. A disadvantage of this known method, however, is that lyophilization of a batch of granules often results in a substantial distribution of the effective content of the granules, even if the granules are extremely uniform in terms of effective content just prior to the drying step. Second, the clustering of particles may occur during the drying step.
由WO 2006/008006也得知一種冷凍乾燥含有藥學化合物之顆粒的方法。為了達成均勻乾燥的條件及防止顆粒群集，推薦使容納欲被乾燥之顆粒的容器連續震動。然而，因為冷凍乾燥顆粒之機械安定性一般不是極高的，建議在規律之間隔下震動含顆粒之容器。此方法之重要的缺點是：顆粒本身易於被破裂且得到很多細顆粒狀材料。而此種細顆粒狀材料是難以處置的。再者，為要在乾燥期間能夠震動容納顆粒之容器，冷凍乾燥裝置整體被震動。因這理由，不能使用標準裝置，因而使該方法在經濟上極不具吸引力。A method of lyophilizing granules containing a pharmaceutical compound is also known from WO 2006/008006. In order to achieve uniform drying conditions and to prevent particle clustering, it is recommended to continuously vibrate the container containing the particles to be dried. However, since the mechanical stability of freeze-dried granules is generally not extremely high, it is recommended to vibrate the container containing the granules at regular intervals. An important disadvantage of this method is that the particles themselves are easily broken and many fine particulate materials are obtained. Such fine particulate materials are difficult to handle. Further, in order to vibrate the container for accommodating the particles during drying, the freeze-drying device as a whole is shaken. For this reason, standard equipment cannot be used, making the method extremely uneconomical.
本發明之目的是要克服或至少減輕先前技藝之方法的缺點。就此而論，已發明一種方法，其包含提供一具有底部及側壁之導熱容器；以顆粒床填充該容器，該床包含多層顆粒且具有不少於1之縱橫比；在顆粒頂層上方提供熱源，該熱源具有一朝向床的頂層之表面，該表面具有至少0.4之發射係數；使容器中所填充之顆粒減壓；至少加熱容器之底部及該表面以提供熱給顆粒，以在減壓下支持冷凍液體之昇華；及在冷凍液體被昇華之後，停止提供熱給顆粒。It is an object of the present invention to overcome or at least alleviate the disadvantages of the prior art methods. In this connection, a method has been devised comprising providing a thermally conductive container having a bottom and a side wall; filling the container with a bed of particles comprising a plurality of layers of particles and having an aspect ratio of not less than one; providing a heat source above the top layer of the particle, The heat source has a surface facing the top layer of the bed, the surface having an emissivity of at least 0.4; decompressing the particles filled in the container; at least heating the bottom of the container and the surface to provide heat to the particles for support under reduced pressure Sublimation of the frozen liquid; and after the frozen liquid is sublimed, the supply of heat to the particles is stopped.
在本方法中，冷凍顆粒要被冷凍乾燥。在此意義上“冷凍顆粒”一詞意為：使在室溫下為液態之顆粒構份成為非液態，且因此可以被認為是冷凍液體。此種狀態可以是結晶者、非結晶者或二者之混合物。冷凍顆粒被置於導熱容器中，例如不具有蓋子但在上方係開放的容器形式。顆粒在容器中形成床，此床包含多層顆粒，典型(但不必須)是2至10層。床之縱橫比(亦即床之寬度對床之高度的比例)應不低於1。這顯然改良本發明之乾燥效能(特別是效率)。顆粒而後進行減壓，之後藉至少加熱容器之底部(該容器至少藉由傳導傳熱給顆粒)及加熱在容器上方所提供之表面(該表面藉由輻射提供熱給顆粒)而供應熱給顆粒。此表面具有至少0.4，較佳地甚至具有0.7或更高之發射係數。在此方面，發射係數(經常以ε指明)是由該表面所輻射之能量對由相同溫度之真黑體所輻射之能量的比例。彼是吸收及輻射能量之能力的量度。真黑體會具有ε=1，然而任何實際表面或物體會具有ε<1。放射係數是一數值且是無單位。藉著具有至少0.4之發射係數，經加熱之表面輻射出相當高之熱量給顆粒。藉提供足夠的熱，冷凍液體在減壓下維持昇華(如此技藝中普遍已知的)且顆粒被乾燥(亦即顆粒損失實質部份之冷凍液體)。典型地，可以含有少於5%，較佳地少於3%，且甚至更佳地少於1.5重量%之殘餘水含量。然而，依照藥學化合物及顆粒之所要的用途，較高的含量可以是令人滿意。一旦達到適合程度之殘餘水含量，此方法被視為完成。而後可以停止提供熱給顆粒，以防止顆粒溫度上升。在此階段，冷凍液體就本發明之意義而言據說是已被昇華，即使冷凍液體之殘餘材料可能仍含於粒子中。本發明顯然是有效、簡單及經濟上吸引人之方式，且仍提供極均勻之乾燥性質。可以獲得冷凍乾燥之顆粒，且在乾燥方法期間不形成或至少相當少地形成群集體。In the method, the frozen particles are to be lyophilized. The term "frozen particles" in this sense means that the particle fraction which is liquid at room temperature becomes non-liquid and can therefore be considered a frozen liquid. Such a state may be a crystallizer, an amorphous one, or a mixture of the two. The frozen granules are placed in a thermally conductive container, for example in the form of a container that does not have a lid but is open at the top. The granules form a bed in the vessel which contains a plurality of layers of particles, typically (but not necessarily) from 2 to 10 layers. The aspect ratio of the bed (ie, the ratio of the width of the bed to the height of the bed) should not be less than one. This obviously improves the drying performance (especially efficiency) of the present invention. The granules are then depressurized and then supplied to the granules by at least heating the bottom of the vessel (which at least transfers heat to the granules by conduction) and heating the surface provided above the vessel which provides heat to the granules by irradiation. . This surface has an emissivity of at least 0.4, preferably even 0.7 or higher. In this respect, the emission coefficient (often indicated by ε) is the ratio of the energy radiated by the surface to the energy radiated by the true black body of the same temperature. He is a measure of the ability to absorb and radiate energy. The true black body will have ε=1, however any actual surface or object will have ε<1. The coefficient of radioactivity is a value and is unitless. By having an emissivity of at least 0.4, the heated surface radiates a relatively high amount of heat to the particles. By providing sufficient heat, the frozen liquid maintains sublimation under reduced pressure (as is generally known in the art) and the particles are dried (i.e., the particles lose a substantial portion of the frozen liquid). Typically, it may contain less than 5%, preferably less than 3%, and even more preferably less than 1.5% by weight of residual water content. However, higher levels may be desirable depending on the intended use of the pharmaceutical compound and the granules. Once the appropriate level of residual water content is reached, this method is considered complete. The supply of heat to the particles can then be stopped to prevent the temperature of the particles from rising. At this stage, the frozen liquid is said to have been sublimated in the sense of the present invention, even though the residual material of the frozen liquid may still be contained in the particles. The present invention is clearly an effective, simple and economically attractive means and still provides extremely uniform drying properties. Freeze-dried granules can be obtained and no or at least relatively small formation of clusters during the drying process.
本發明可以有利地應用於多種藥學化合物。此類化合物可以是例如微生物(例如細菌、病毒、列克次屬體、原生動物)或由彼等所衍生之亞單元，可由自然界獲得或經由重組技術而製成；但此化合物也可以是藥物，例如合成的藥物。已配製於冷凍顆粒中之藥物的實例由EP 0 695 171及US 3,932,943得知。在每一情況中，所得之優點，特別是與乾燥方法之物理特徵有關者，對於獲得高品質之最終產物是重要的。The present invention can be advantageously applied to various pharmaceutical compounds. Such compounds may be, for example, microorganisms (eg, bacteria, viruses, Leques, protozoa) or subunits derived therefrom, which may be obtained by nature or by recombinant techniques; however, the compounds may also be pharmaceuticals For example, synthetic drugs. Examples of drugs that have been formulated in frozen granules are known from EP 0 695 171 and US Pat. No. 3,932,943. In each case, the advantages obtained, particularly in relation to the physical characteristics of the drying process, are important to obtain a high quality end product.
要注意：於冷凍乾燥方法中應用輻射本身在此技藝中是已知的。例如，在Drying Technology,Vol. 21,No. 2,pp. 249-263,2003中描述：可以使用輻射以充分地加熱欲被乾燥之化合物。然而，由此參考資料顯明：輻射是傳導之唯一代替且提供相同之乾燥結果。因此，令申請人驚訝地：在如申請專利範圍第1項中所定義之條件下，傳導(亦即藉由與容器之經加熱的底部接觸而提供熱給顆粒)及輻射之組合使用，提供乾燥顆粒材料實質上不同的結果，亦即較少或無群集體出現且可以提供均勻的有效含量。It is to be noted that the application of radiation itself in freeze-drying processes is known per se in the art. For example, it is described in Drying Technology, Vol. 21, No. 2, pp. 249-263, 2003 that radiation can be used to sufficiently heat the compound to be dried. However, this reference shows that radiation is the only substitute for conduction and provides the same drying result. Therefore, the Applicant was surprised to: in combination with the use of radiation (i.e., by providing heat to the particles in contact with the heated bottom of the vessel) and radiation, as provided in the scope of claim 1 The dry particulate material results in substantially different, i.e., fewer or no clusters appear and can provide a uniform effective level.
在一具體實施方式中，床之縱橫比不少於5，特別是不少於10。顯然地，這些較佳之比例之提供本發明獲得較高之生產量且不損失乾燥品質之可能性。In a specific embodiment, the aspect ratio of the bed is not less than 5, particularly not less than 10. Obviously, these preferred ratios provide the possibility that the present invention achieves higher throughput without loss of dry quality.
在容器之底部及側壁各具有一面向粒子床的表面的本發明之另一具體實施方式中，這些表面分別具有至少0.4，特別是至少0.7之發射係數。此方式，不僅可以藉由傳導也可藉由輻射提供足夠熱量給顆粒。顯然地，藉使用此類之容器，可以獲得極佳之乾燥結果。較佳地，熱源之發射係數比容器底部及側壁有相同或更高之發射係數。In another embodiment of the invention in which the bottom and side walls of the container each have a surface facing the particle bed, the surfaces each have an emissivity of at least 0.4, in particular at least 0.7. In this way, not only can the particles be supplied with sufficient heat by conduction but also by radiation. Obviously, by using such a container, excellent drying results can be obtained. Preferably, the heat source has an emission coefficient that is the same or higher than the bottom and side walls of the container.
在容器底部係藉使用第一加熱板以作為在顆粒頂層上方的熱源的具體實施方式中，使用第二加熱板。這獲得簡單構造之冷凍乾燥裝置，而且無須損及本發明之任何優點。再者，特別在均勻地被加熱時，板具有能極均勻地輻射熱至其周圍的優點。當使用例如加熱帶或線圈以作為輻射加熱元件時，會較不容易提供一種在顆粒床之每一位置上輻射出約相同量之輻射的輻射源。In a specific embodiment where the first heating plate is used at the bottom of the container as a heat source above the top layer of the particles, a second heating plate is used. This results in a freeze-drying device of a simple construction without compromising any of the advantages of the present invention. Furthermore, the plate has the advantage of being able to radiate heat to its surroundings very uniformly, particularly when heated uniformly. When, for example, a heating belt or coil is used as the radiant heating element, it may be less desirable to provide a source of radiation that radiates about the same amount of radiation at each location of the bed of particles.
在第二加熱板基本上具有與第一加熱板相同組成的另一具體實施方式中，在第二板之面向頂層之側面提供以具有至少0.4之發射係數的材料。以此方式，使用標準乾燥裝置可以獲得本發明之優點。在一具體實施方式中，第二加熱板之下側提供一可提供該發射係數的塗層。或者，可在第二加熱板之下側提供以另外之具有該發射係數的板。不證自明地，塗層或另外之板應與第二加熱板有良好之熱接觸。對塗層而言，這是固有的。在另外之板的情況中，應確定有良好的熱接觸，例如使用任何技藝已知的技術，例如使用導熱膠、使用黏合表面之極緊密機械方式(例如焊接)或任何其他技術。In another embodiment in which the second heating plate has substantially the same composition as the first heating plate, a material having an emission coefficient of at least 0.4 is provided on the side of the second plate facing the top layer. In this way, the advantages of the present invention can be obtained using a standard drying device. In a specific embodiment, the underside of the second heating plate provides a coating that provides the emissivity. Alternatively, a plate having the other emission coefficient may be provided on the lower side of the second heating plate. It is self-evident that the coating or other board should have good thermal contact with the second heating plate. This is inherent to the coating. In the case of additional sheets, good thermal contact should be determined, for example using any technique known in the art, such as the use of thermally conductive adhesives, extremely close mechanical means of bonding surfaces (e.g., welding), or any other technique.
在欲使用另外之板的情況中，較佳地，此板係由氟聚合物製成，特別係由聚四氟乙烯(PTFE)製成。藉使用氟聚合物以構成此板，可以提供相當便宜之板，但此板仍具有極良好之可清潔性，這在含藥物之顆粒被冷凍乾燥之情況中是一重要優點。In the case where an additional plate is to be used, preferably, the plate is made of a fluoropolymer, in particular, made of polytetrafluoroethylene (PTFE). By using a fluoropolymer to form the board, a relatively inexpensive board can be provided, but the board still has excellent cleanability, which is an important advantage in the case where the drug-containing particles are freeze-dried.
在一具體實施方式中，藉由加熱第一加熱板至與第二加熱板相同之溫度，提供熱給顆粒。這簡化冷凍乾燥方法之控制。再者，可以使用第二加熱板作為熱源，以加熱第二容器之底部至與第一容器底部相同之溫度。In one embodiment, heat is supplied to the particles by heating the first heating plate to the same temperature as the second heating plate. This simplifies the control of the freeze drying process. Further, a second heating plate can be used as a heat source to heat the bottom of the second container to the same temperature as the bottom of the first container.
要注意：本發明也關於一種藥學包，其包含容器，例如小瓶、管、注射器、泡罩包裝(blister)等，且該容器中具有至少一種藉由依本發明之方法所得的顆粒。特別地，本發明係關於一種容器，其中含有一或多種冷凍乾燥顆粒，該顆粒含有抗原(意即一種引發且調停對應之免疫體的形成的物質，經常是一種微生物及/或可由彼所衍生之亞單元，可經由基本上生物技術或經由再構成技術之使用而獲得)，且可被再構成以作為口服或非經腸投服之疫苗的部份。It is to be noted that the invention also relates to a pharmaceutical pack comprising a container, such as a vial, tube, syringe, blister, etc., and having at least one particle obtained by the method of the invention. In particular, the present invention relates to a container comprising one or more freeze-dried granules containing an antigen (ie, a substance that initiates and mediates the formation of a corresponding immunological body, often a microorganism and/or may be derived therefrom The subunits are available via substantially biotechnology or via the use of reconstitution techniques and can be reconstituted as part of an oral or parenteral vaccine.
本發明現將使用以下實例及圖示以另外說明。The invention will now be further illustrated using the following examples and illustrations.
實例1描述多種獲得含一或多種藥物之冷凍顆粒的方法。Example 1 describes various methods of obtaining frozen particles containing one or more drugs.
實例2連同圖1(其概略地說明冷凍乾燥器)及圖2(其概略地說明容器)描述用於本發明之冷凍乾燥裝置。Example 2 describes a freeze-drying apparatus for use in the present invention, together with Figure 1 (which schematically illustrates a freeze dryer) and Figure 2 (which schematically illustrates a container).
實例3描述一種適於冷凍乾燥經冷凍之顆粒的方法及所得之結果。Example 3 describes a method suitable for freeze drying frozen pellets and the results obtained.
實例4描述用於測量多種表面之發射係數的方法。Example 4 describes a method for measuring the emission coefficients of various surfaces.
在此技藝中普遍已知如何生產含有藥物之冷凍顆粒。這描述於例如EP 799613(讓與AKZO Nobel NV)，JP 09248177(讓與Snow Brand Milk Corp)及WO 2006/008006(讓與Bayer Technology Services GmbH)。也從這些參考資料得知：此種顆粒可被冷凍乾燥以獲得“乾的”且安定的顆粒。在後項參考資料中，提及很多用於生產冷凍顆粒之可選擇的方法。開始於第4頁第23行(“There are many methods known to those skilled in the art....”(許多方法已為熟悉此項的人士所習知))且結束於第8頁第13行(“...The process is suitable for frozen granules or pellets.”(這些方法適合於冷凍顆粒或丸狀物))，這些方法被總結。在這些已知方法之後，已知很多其他方法以獲得含有藥學化合物於其中之冷凍丸狀物，且導致球形顆粒或其他形狀之成形顆粒。在該情況中，已使用由JP 09248177得知之技術，以獲得具有約6毫米平均直徑之冷凍球形丸狀物。最常使用在1至15毫米間之尺寸，特別是在2至10毫米間之尺寸。It is generally known in the art how to produce frozen particles containing a drug. This is described, for example, in EP 799613 (for AKZO Nobel NV), JP 09248177 (for Snow Brand Milk Corp) and WO 2006/008006 (for Bayer Technology Services GmbH). It is also known from these references that such particles can be freeze dried to obtain "dry" and stable particles. In the latter reference, many alternative methods for producing frozen granules are mentioned. Beginning on page 4, line 23 ("There are many methods known to those skilled in the art..." (many methods are known to those familiar with this item) and end on page 8, line 13 ("The process is suitable for frozen granules or pellets." These methods are summarized. Following these known methods, many other methods are known to obtain frozen pellets containing the pharmaceutical compound therein, and to result in spherical particles or other shaped shaped particles. In this case, the technique known from JP 09248177 has been used to obtain frozen spherical pellets having an average diameter of about 6 mm. It is most often used in sizes between 1 and 15 mm, especially between 2 and 10 mm.
注意：液體原則上可以是任何液體。在很多情況中，液體之主要構份是水。通常，液體是在化合物生產方法中用於藥學化合物之載劑。然而，液體也可以作為介質而被添加至化合物，以供獲得容易被處理以獲得冷凍顆粒之組成。在藥學化合物是微生物或其亞單元的情況中，液體通常實質上是由發酵汁或其例如上清液之部份(例如在化合物產自工業發酵器的情況中)或尿囊流體(例如在化合物產自蛋發酵的情況中)所組成，且任意包含用於提供例如良好處理性質或所要之最終產物性質(例如儲存安定性)的另外的流體及/或其他構份。Note: The liquid can in principle be any liquid. In many cases, the primary component of the liquid is water. Generally, a liquid is a carrier for a pharmaceutical compound in a method of producing a compound. However, the liquid can also be added to the compound as a medium for obtaining a composition that is easily processed to obtain frozen particles. Where the pharmaceutical compound is a microorganism or a subunit thereof, the liquid is typically substantially derived from the fermented juice or a portion thereof such as a supernatant (eg, in the case where the compound is produced from an industrial fermenter) or an allantois fluid (eg, The compound is produced from the case of egg fermentation and optionally contains additional fluids and/or other components for providing, for example, good handling properties or desired final product properties (e.g., storage stability).
在圖1中，概略地說明冷凍乾燥器(冷凍乾燥裝置)。此種冷凍乾燥器可以是例如得自Salm en Kipp,Breukelen,The Netherlands之Christ Epsilon 2-12D。冷凍乾燥器1包含殼體2及多個擱板3。Epsilon 2-12D包含4+1個擱板；為方便之故，三個這些擱板(意即擱板3a、3b及3c)顯示於圖1中。這些擱板各自提供以加熱元件5(分別指稱為5a、5b及5c)，以均勻地加熱擱板3。藉使用處理單元10以控制加熱。殼體連結至泵單元11，以在殼體2內提供適當之低壓。殼體內部可以藉使用冷卻單元12(特別是含有冷凝器者)冷卻低至-60℃之溫度。擱板3a及3b提供以黑色PTFE板8及8’並固定於其底部。這些板之發射係數是0.78。藉這些黑色板與擱板間之緊密接觸，這些板最終可被加熱至與擱板本身相同之溫度。以此方式，板8可視為附加至擱板3本身之加熱源。In Fig. 1, a freeze dryer (freeze dryer) will be schematically explained. Such a freeze dryer can be, for example, Christ Epsilon 2-12D from Salm en Kipp, Breukelen, The Netherlands. The freeze dryer 1 includes a housing 2 and a plurality of shelves 3. The Epsilon 2-12D contains 4+1 shelves; for convenience, three of these shelves (i.e., shelves 3a, 3b, and 3c) are shown in FIG. These shelves are each provided with heating elements 5 (referred to as 5a, 5b, and 5c, respectively) to uniformly heat the shelf 3. The processing unit 10 is used to control the heating. The housing is coupled to the pump unit 11 to provide a suitable low pressure within the housing 2. The interior of the housing can be cooled to a temperature as low as -60 ° C by means of a cooling unit 12, in particular a condenser. The shelves 3a and 3b are provided with black PTFE sheets 8 and 8' and fixed to the bottom thereof. The emission coefficient of these plates is 0.78. By intimate contact between the black plates and the shelves, the plates can ultimately be heated to the same temperature as the shelves themselves. In this way, the plate 8 can be considered as a heating source attached to the shelf 3 itself.
容器15及15’置於擱板上。這些容器是由導熱材料製成，在此情況中是由填充碳黑之聚對苯二甲酸乙二酯所製成。容器與擱板(其上放置該容器)有導熱接觸。容器填充以冷凍顆粒30，該等顆粒因此形成填充顆粒床29於每一容器中。藉加熱擱板，顆粒可以經由被加熱之容器底部及側壁而受熱，及分別藉由被加熱之板8及8’的輻射而受熱。圖2提供容器15本身之視圖。每一容器包含底部21及側壁20。典型地，容器具有約20至30公分之寬度及長度以及約4公分之高度。在填充容器後，填充床高度通常是1.5至3公分。這導致在20/3=7至約30/1.5=20之床的縱橫比的典型值。Containers 15 and 15' are placed on the shelf. These containers are made of a thermally conductive material, in this case made of polyethylene terephthalate filled with carbon black. The container is in thermal contact with the shelf on which the container is placed. The container is filled with frozen particles 30 which thus form a bed of packed particles 29 in each container. By means of the heated shelf, the particles can be heated by the bottom and side walls of the heated container and heated by the radiation of the heated plates 8 and 8', respectively. Figure 2 provides a view of the container 15 itself. Each container includes a bottom portion 21 and a side wall 20. Typically, the container has a width and length of from about 20 to 30 centimeters and a height of about 4 centimeters. After filling the container, the height of the packed bed is typically 1.5 to 3 cm. This results in a typical value of the aspect ratio of the bed at 20/3 = 7 to about 30/1.5 = 20.
在此實例中，具有高發射係數之熱源是PTFE板8(及8’)。或者，擱板可能已提供黑漆，以提供0.4或更高之發射係數。另一可能性會是已化學地改變(例如藉由蝕刻)及/或機械地改變(例如藉由砂磨或砂噴)擱板3表面(在Epsilon 2-12D的情況其係由不鏽鋼鋼製成)，以提供恰當的發射係數。In this example, the heat source having a high emissivity is the PTFE plate 8 (and 8'). Alternatively, the shelf may have been provided with black paint to provide an emission factor of 0.4 or higher. Another possibility would be that the surface of the shelf 3 has been chemically altered (for example by etching) and/or mechanically changed (for example by sanding or sandblasting) (in the case of Epsilon 2-12D it is made of stainless steel) In order to provide an appropriate emission coefficient.
在一可替代冷凍乾燥器中，容器15藉由輻射來加熱。雖然因便利性及速度，傳導係更佳的；但經由每一容器下方之輻射加熱器元件來加熱容器也是一種可用的選擇。該加熱器則可用來提供熱給位於該加熱器元件下方之冷凍顆粒填充床的頂層。In an alternative freeze dryer, the vessel 15 is heated by radiation. Although the conduction system is better for convenience and speed; heating the container via the radiant heater element below each container is also a useful option. The heater can then be used to provide heat to the top layer of the frozen particle packed bed located below the heater element.
容器可以由多種導熱材料所製成，例如由塑膠、玻璃、金屬或甚至複合材料所製成。較佳地，容器頂部是開放的，以使經昇華之氣體可以容易地從填充床逸出。然而，已描述：當此容器基本上是密閉的且僅含有孔於蓋子中以釋出經昇華之材料時，經昇華之載劑液體也可以成功地從容器中除去。附帶蓋子之容器的優點是蓋子本身可以作為輻射熱源。The container can be made of a variety of thermally conductive materials, such as plastic, glass, metal or even composite materials. Preferably, the top of the container is open so that the sublimed gas can readily escape from the packed bed. However, it has been described that the sublimated carrier liquid can also be successfully removed from the container when the container is substantially airtight and contains only holes in the lid to release the sublimed material. The advantage of a container with a lid is that the lid itself can act as a source of radiant heat.
為了獲得冷凍乾燥顆粒，使用如實例1中所提及之方法及Christ Epsilon 2-12D冷凍乾燥器，該冷凍乾燥器具有如實例2中所述之高發射係數表面。為了獲得冷凍顆粒，在此實例中從蛋中收集活的病毒。在一些情況中(亦即用於IB及ND病毒，參見表2)，含有病毒且與安定劑混合之尿囊流體被冷凍成球形丸狀物；在其他情況中(意即用於Gumboro型病毒，參見表2)，在被過濾且已添加安定劑之後，雞胚流體被冷凍成球形丸狀物。冷凍顆粒(具有約-60℃之溫度)置於容器中(如實例2中所述的)，以獲得具有約15之縱橫比的填充床。容器而後置於溫度已達約-35℃之冷凍乾燥器中。冷凍乾燥器進行以下冷凍乾燥循環(表1)。To obtain freeze-dried granules, the method as mentioned in Example 1 and a Christ Epsilon 2-12D freeze dryer having a high emissivity surface as described in Example 2 was used. In order to obtain frozen particles, live virus is collected from the eggs in this example. In some cases (ie for IB and ND viruses, see Table 2), the allantois fluid containing the virus and mixed with the tranquilizer is frozen into spherical pellets; in other cases (ie for the Gumboro virus) , see Table 2), after being filtered and the stabilizer has been added, the chicken embryo fluid is frozen into spherical pellets. Frozen pellets (having a temperature of about -60 °C) were placed in a container (as described in Example 2) to obtain a packed bed having an aspect ratio of about 15. The container is then placed in a freeze dryer having a temperature of about -35 °C. The freeze dryer was subjected to the following freeze-drying cycle (Table 1).
如表1中可見的，在擱板裝載經填充的容器之後，擱板首先保持在-35℃下30分鐘(“冷凍”期)。在此，顆粒溫度達到-35℃。壓力保持在大氣壓下。而後，擱板溫度在20分鐘內安定在-35℃下，壓力仍是大氣壓(“製備”)。而後，壓力在10分鐘內降至0.370毫巴，擱板溫度保持在-35℃下(“起始昇華”)。在這些條件下，冷凍液體己昇華且經由熱源將熱供應至顆粒。然而，這些條件下之昇華速度相當低。為了增加昇華速度，擱板在3小時內升至40℃(“昇華1”)，且保持在該溫度下16小時(“昇華2”)。壓力保持低至0.370毫巴的值。在此之後，壓力進一步降至0.021毫巴，同時擱板溫度降至4℃。後項步驟進行1分鐘(“密閉步驟”)。在那之後，昇華方法被完成且約98%之冷凍液體己離開顆粒。而後，將溫度約20℃之經乾燥的氮氣導入冷凍乾燥器中直至壓力約為大氣壓。此進行約2分鐘。而後，門可以被敞開以取出經乾燥之顆粒。當使用本方法時，可以見到：可以獲得均勻之冷凍乾燥結果，可觀察到均勻的冷凍乾燥顆粒床形式。在敞開冷凍乾燥器後，不使顆粒處於潮濕環境以嘗試防止水冷凝在顆粒上。特別地，在含有乾空氣之環境的櫥內，顆粒被填充於小容器中。在填充容器後，容器被密封且儲存在涼的地方(4-8℃)直至進一步的使用。As can be seen in Table 1, after the shelf was loaded with the filled container, the shelf was first held at -35 °C for 30 minutes ("freezing" period). Here, the particle temperature reached -35 °C. The pressure is maintained at atmospheric pressure. The shelf temperature was then stabilized at -35 ° C for 20 minutes and the pressure was still atmospheric ("preparation"). Thereafter, the pressure dropped to 0.370 mbar in 10 minutes and the shelf temperature was maintained at -35 ° C ("initial sublimation"). Under these conditions, the frozen liquid has sublimed and heat is supplied to the particles via a heat source. However, the sublimation speed under these conditions is quite low. In order to increase the sublimation speed, the shelf rose to 40 ° C ("sublimation 1") within 3 hours and remained at this temperature for 16 hours ("sublimation 2"). The pressure is kept as low as 0.370 mbar. After this, the pressure was further reduced to 0.021 mbar while the shelf temperature dropped to 4 °C. The next step is performed for 1 minute ("sealing step"). After that, the sublimation process was completed and about 98% of the frozen liquid had left the granules. Thereafter, the dried nitrogen gas having a temperature of about 20 ° C is introduced into the freeze dryer until the pressure is about atmospheric pressure. This takes about 2 minutes. The door can then be opened to remove the dried particles. When using this method, it can be seen that a uniform freeze-drying result can be obtained and a uniform freeze-dried particle bed form can be observed. After opening the freeze dryer, the particles are not allowed to be exposed to moisture in an attempt to prevent condensation of water on the particles. In particular, in a cabinet containing an environment of dry air, the granules are filled in a small container. After filling the container, the container is sealed and stored in a cool place (4-8 ° C) until further use.
以此方式，獲得經冷凍乾燥之球狀物，其具有約6毫米之直徑且其中具有如表2中所示之藥學化合物。這些冷凍乾燥顆粒之總組成，特別是形成用於藥學成份之載劑材料的化合物，基本上同於對應之疫苗的冷凍乾燥丸狀物，該對應的疫苗係得自Intervet Nederland b.v.,Boxmeer,The Netherlands(對應之產品名稱也在表2中指明)。In this manner, a lyophilized pellet having a diameter of about 6 mm and having a pharmaceutical compound as shown in Table 2 was obtained. The total composition of these freeze-dried granules, particularly the compound forming the carrier material for the pharmaceutical ingredient, is substantially the same as the freeze-dried pellet of the corresponding vaccine obtained from Intervet Nederland bv, Boxmeer, The Netherlands (corresponding product names are also indicated in Table 2).
雖然本發明之方法已藉由使用活病毒作為冷凍乾燥顆粒中所含之藥學化合物而特別地例示，熟知此項技藝者可以明白：當顆粒中含有其他形式之藥學化合物(例如其他之微生物、活性分子、微生物之亞單元或任何其他藥學化合物)之時，亦可以得到本發明之優點(特別是均勻之乾燥結果)。Although the method of the present invention has been specifically exemplified by using a live virus as a pharmaceutical compound contained in the freeze-dried granules, it is understood by those skilled in the art that when the granule contains other forms of pharmaceutically acceptable compounds (e.g., other microorganisms, activity) The advantages of the invention (especially uniform drying results) can also be obtained at the time of the molecule, the subunit of the microorganism or any other pharmaceutical compound.
使用經冷凍乾燥之顆粒以提供藥學包。此包係由含有一或多種經冷凍乾燥之顆粒及任意之其他構份的容器(例如玻璃或塑膠管瓶)所組成。在經冷凍乾燥之顆粒中的藥學化合物可以藉直接口服顆粒本身而投服至病人，但也可能例如利用液體再構成顆粒，以致獲得一種適合飲用或經由注射流體而非經腸投服(例如皮下、肌內、黏膜下及皮內投服)之組成物。The lyophilized granules are used to provide a pharmaceutical pack. The package consists of a container (eg, a glass or plastic vial) containing one or more lyophilized granules and any other constituents. The pharmaceutical compound in the lyophilized granules can be administered to the patient by direct oral administration of the granules themselves, but it is also possible, for example, to reconstitute the granules with a liquid, such that a suitable drink is obtained or administered via an injection fluid rather than enterally (for example subcutaneously) , intramuscular, submucosal and intradermal administration of the composition.
本發明定義中之發射率是平均發射率，其係在四個不同之表面溫度(意即55、60、65及70℃)下建立的。發射率可以藉使用商業上可得之專門的發射率測量裝置，例如Advanced Fuel Research Inc.,East Hartford,CT USA之Model 205WB來測量。然而此種裝置是極昂貴的。或者，如普遍已知的，測量發射率之極簡單的方式是加熱該表面及具有已知發射率的表面至相同溫度，如藉由熱電偶所測得的。而後，用標準紅外線高溫計讀取二表面之溫度。此二個紅外溫度測量的差異是因表面之發射率的差異(也參見Applied Optics,Vol. 13,No 9,September 1974)。吾人選擇此方法以獲得用於本實驗中之各種形式之表面的發射係數。所得之結果示於表2。The emissivity in the definition of the invention is the average emissivity, which is established at four different surface temperatures (i.e., 55, 60, 65, and 70 ° C). The emissivity can be measured by using a commercially available specific emissivity measuring device such as Model 205WB of Advanced Fuel Research Inc., East Hartford, CT USA. However, such a device is extremely expensive. Alternatively, as is generally known, a very simple way to measure emissivity is to heat the surface and a surface having a known emissivity to the same temperature, as measured by a thermocouple. The temperature of the two surfaces is then read using a standard infrared pyrometer. The difference in these two infrared temperature measurements is due to the difference in emissivity of the surface (see also Applied Optics, Vol. 13, No 9, September 1974). We chose this method to obtain the emission coefficients for the various forms of surfaces used in this experiment. The results obtained are shown in Table 2.
明顯地，當使用具有0.4或更高之發射係數的表面時，可以獲得本方法之優點。事實上，冰並非極實用之選擇，因為此材料在冷凍乾燥器中之板所用的一般溫度下會昇華或甚至熔化。Obviously, when a surface having an emission coefficient of 0.4 or higher is used, the advantages of the method can be obtained. In fact, ice is not a very practical choice because it will sublime or even melt at the normal temperatures used in the plates in the freeze dryer.
1．．．冷凍乾燥器1. . . Freeze dryer
2．．．殼體2. . . case
3．．．擱板3. . . shelf
5．．．加熱元件5. . . Heating element
10．．．處理單元10. . . Processing unit
11．．．泵單元11. . . Pump unit
12．．．冷卻單元12. . . Cooling unit
8,8’．．．黑色PTFE板8,8’. . . Black PTFE board
15,15’．．．容器15,15’. . . container
20．．．側壁20. . . Side wall
21．．．底部twenty one. . . bottom
29．．．填充顆粒床29. . . Filled particle bed
30．．．冷凍顆粒30. . . Frozen granule
圖1概略地說明依本發明之冷凍乾燥器。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic illustration of a freeze dryer in accordance with the present invention.
圖2概略地說明依本發明之冷凍乾燥器的容器。Figure 2 is a schematic illustration of a container of a freeze dryer in accordance with the present invention.
1．．．冷凍乾燥器1. . . Freeze dryer
2．．．殼體2. . . case
10．．．處理單元10. . . Processing unit
11．．．泵單元11. . . Pump unit
12．．．冷卻單元12. . . Cooling unit
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| TWI436789B (en) * | 2008-01-21 | 2014-05-11 | Intervet Int Bv | Method for lyophilising particles having a pharmaceutical compound contained therein and a pharmaceutical pack containing such particles |
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| JP2011510252A (en) | 2011-03-31 |
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